MAGNETIC LEVITATION SYSTEM
A magnetic levitation system is described, including a first and second magnets having surfaces of their like-poles facing each other; and a container disposed between the first and second magnets' like poles and containing a solution including a paramagnetic complex in a non-aqueous solvent, where the paramagnetic complex includes a paramagnetic metal and at least one ligand that coordinates to the paramagnetic metal via electron donation. Methods of separating a mixture of solid compounds, and/or identifying, confirming, and/or predicting the composition of the mixture, are also described.
This application claims priority to U.S. Provisional Patent Application No. 62/819,382, filed Mar. 15, 2019, which is hereby incorporated by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENTThe present invention was made with government support from the Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering (Award No. ER45862), and from Department of Defense, Defense Advanced Research Projects Agency (Award No. W911NF-18-2-0030). The U.S. Government has certain rights in the invention.
INCORPORATION BY REFERENCEAll patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described therein.
FIELD OF THE INVENTIONThe present disclosure relates generally to the field of analytical chemistry. More particularly, the present disclosure relates to density analysis.
SUMMARY OF THE INVENTIONIn one aspect, a magnetic levitation system includes:
a first and second magnets having surfaces of their like-poles facing each other; and
a container disposed between the first and second magnets' like poles and containing a solution including a paramagnetic complex in a non-aqueous solvent; where the paramagnetic complex includes a paramagnetic metal and at least one ligand that coordinates to the paramagnetic metal via electron donation.
In any one of the embodiments described herein, the paramagnetic complex has the structure
where M is a paramagnetic metal and L1, L2, L3, L4, L5, L6, L7, and L8 are ligands that coordinate to the paramagnetic metal via electron donation.
In any one of the embodiments described herein, L1, L2, L3, L4, L5, L6, L7, and L8 are independently selected from the group consisting of substituted or unsubstituted phosphine oxides, oxazoles, imidazoles, pyridines, diamines, bipyridines, phenanthrolines, diketonates, malonamides, malonates, β-ketoesters, β-ketoamides, carboxylates, dicarboxylates, and ethylenediaminetetraacetic acid.
In any one of the embodiments described herein, two or more of L1, L2, L3, L4, L5, L6, L7, and L8 are covalently bonded to a substituent group consisting of 1-20 carbon atoms.
In any one of the embodiments described herein, at least one of L1, L2, L3, L4, L5, L6, L7, and L8 includes
where each occurrence R1 is independently H, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
In any one of the embodiments described herein, the paramagnetic complex has the structure
where n is an integer from 1-7 and where
denotes the group consisting of 1-20 carbon atoms.
In any one of the embodiments described herein,
are independently selected from the group consisting of 2,2′-dipyridyl, optionally substituted with one or more R1, 1,10-phenanthrenyl, optionally substituted with one or more R1, and
where each occurrence of R2 is independently H, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
In any one of the embodiments described herein, the paramagnetic complex has the structure,
In any one of the embodiments described herein, the paramagnetic complex has the structure
In any one of the embodiments described herein, each occurrence of R1 and R2 is independently (C1-C10)alkyl or (C6-C10)aryl.
In any one of the embodiments described herein, each occurrence of R1 and R2 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, or isomers thereof.
In any one of the embodiments described herein, each occurrence of R1 and R2 is independently methyl, butyl, tert-butyl, octyl, or phenyl.
In any one of the embodiments described herein, M is selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, cerium, praseodymium, neodymium, europium, gadolinium, terbium, dysprosium, copper, holmium, erbium, thulium, and lanthanum.
In any one of the embodiments described herein, M is gadolinium.
In any one of the embodiments described herein, the paramagnetic complex is
In any one of the embodiments described herein, the paramagnetic complex is
In any one of the embodiments described herein, the solvent is selected from the group consisting of acyclic and cyclic hydrocarbons, acyclic and cyclic halo- or per-halo hydrocarbons, aromatic hydrocarbons, acyclic and cyclic ethers, and acyclic and cyclic aldehydes, ketones, esters, amides, sulfides, sulfoxides, and sulfones, and a combination thereof.
In any one of the embodiments described herein, the solvent is pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tetrachloroethylene, carbon tetrachloride, dichloromethane, trichloromethane, diethyl ether, tetrahydrofuran, ethyl acetate, butyl acetate, or a combination thereof.
In any one of the embodiments described herein, the solvent is hexane, tetrachloroethylene, or a combination thereof.
In any one of the embodiments described herein, the solvent is tetrachloroethylene.
In any one of the embodiments described herein, the system further includes a camera, or a light source to illuminate the container, or both.
In any one of the embodiments described herein, the container is an open or closed vessel capable of holding the solution.
In any one of the embodiments described herein, the container is made from a glass, a plastic, a polymer, a ceramic, one or more plant-based fibers in a polymer matrix, one or more plant-based fibers in a ceramic matrix, an aerogel, a gel including polar or apolar solvents, a non-ferromagnetic, non-ferrimagnetic, or non-paramagnetic metal, or a combination thereof.
In any one of the embodiments described herein, the container is a cuvette, jar, test tube, centrifuge tube, or capillary tube.
In any one of the embodiments described herein, the container is a cuvette.
In any one of the embodiments described herein, the first and second magnets are each independently selected from the group consisting of a permanent magnet, an electromagnet, and a superconducting magnet.
In any one of the embodiments described herein, the first and second magnets are permanent magnets.
In any one of the embodiments described herein, the first and second magnets are each independently neodymium magnets, samarium-cobalt magnets, ferrite magnets, or Alnico magnets.
In any one of the embodiments described herein, the first and second magnets are each independently shaped as a block, a cylinder, a sphere, a disc, or a ring.
In another aspect, a method of analyzing a sample including one or more solid compounds, the method including:
(a) providing the magnetic levitation system of any one of claims 1-29;
(b) depositing the sample in the solution; and
(c) allowing each of the solid compounds in the sample to migrate to a position in the container indicative of its density.
In any one of the embodiments described herein, the method further includes
(d) analyzing one or more of the solid compounds to determine or confirm its identity.
In any one of the embodiments described herein, step (d) includes positioning the container such that one or more of the compounds contact the wall of the container and analyzing said compound(s) through the wall of the container using a spectrometer.
In any one of the embodiments described herein, step (d) includes removing the one or more solid compounds from the container.
In any one of the embodiments described herein, the one or more solid compounds are removed using a pipette, a siphon, a spoon, a spatula, or a small basket.
In any one of the embodiments described herein, the analysis includes a technique selected from the group consisting of Fourier transform infrared spectroscopy with attenuated total reflectance, mass spectrometry, nuclear magnetic resonance spectroscopy, Raman spectroscopy, X-ray diffractometry, capillary electrophoresis, gas chromatography, ion-mobility spectrometry, liquid chromatography, microcrystalline tests, supercritical fluid chromatography, thin layer chromatography, ultraviolet/visible spectroscopy, microscopy, visual examination, colorimetric tests, fluorescence spectroscopy, immunoassays, melting point analysis, pharmaceutical package inserts, and combinations thereof.
In any one of the embodiments described herein, the technique includes a portable or handheld device.
In any one of the embodiments described herein, the technique is Fourier transform infrared spectroscopy with attenuated total reflectance, Raman spectroscopy, mass spectrometry, X-ray diffractometry, a colorimetric test, or a combination thereof.
In any one of the embodiments described herein, the Raman spectroscopy is conducted using a portable or handheld device.
In any one of the embodiments described herein, the sample is a crystalline or amorphous sample.
In any one of the embodiments described herein, the sample includes one or more controlled substances, adulterants, diluents, or a combination thereof.
In any one of the embodiments described herein, the sample includes fentanyl, acetyl fentanyl, benzyl fentanyl, carfentanyl, cocaine, heroin, oxycodone, methamphetamine, cannabinoids, lysergic acid diethylamide, methaqualone, methadone, hydromorphone, Ritalin, Adderall, peyote, 3,4-methylenedioxymethamphetamine, acetaminophen, caffeine, diltiazem, dipyrone/metamizole, lidocaine, hydroxyzine, levamisole, papaverine, procaine, phenacetin, dimethyl sulfone, D-fructose, D-glucose, α-lactose, D-mannitol, sodium carbonate, starch, including potato starch, sucrose, talc, quinine, butylated hydroxytoluene, hypromellose, polyethylene glycol, polyethylene oxide, magnesium stearate, titanium dioxide, an isomer thereof, a salt thereof, a combination thereof.
In any one of the embodiments described herein, the salt is a sodium, aluminum, potassium, calcium, hydrochloride, citrate, nitrate, sulfate, acetate phosphate, diphosphate, maleate, mesylate, tartrate, or gluconate salt.
In any one of the embodiments described herein, the salt is a hydrochloride salt.
In any one of the embodiments described herein, the sample includes a salt of fentanyl or caffeine.
In any one of the embodiments described herein, the one or more compounds are present in the sample between 0.01 and 100 weight percent.
In any one of the embodiments described herein, the one or more compounds are present in the sample between 0.01 and 10 weight percent.
In any one of the embodiments described herein, the method further includes:
(e) generating a profile of the position of the one or more compounds relative to the container; and
(f) generating a database including a plurality of profiles, each of which corresponds to a known solid compound or a known mixture of solid compounds.
In any one of the embodiments described herein, the profile of the sample and the profiles of the database are determined at a plurality of time points after the sample is deposited in the solution in step (b).
In any one of the embodiments described herein, the method further includes:
(g) comparing the profile of the sample to the profiles in the database.
In any one of the embodiments described herein, step (g) further includes determining the identity of the compound based on the comparison.
In any one of the embodiments described herein, step (g) further includes: using a computer to calculate the distances between the generated profile of the sample and the profiles in the database to identify a profile in the database within a minimum distance to the generated profile; where the distance is a Euclidian or Mahalanobis distance.
In any one of the embodiments described herein, the profile in the database further includes the source of the known solid compound or the known mixture of solid compounds and step (g) further includes determining the source of the sample.
In any one of the embodiments described herein, step (g) further includes determining the particle size or the mixture of particle sizes of the compound.
In any one of the embodiments described herein, the profile in the database further includes a source of the compound and step (g) further includes determining the source of the sample.
In any one of the embodiments described herein, the method includes obtaining and processing spectroscopic, spectrometric, chromatographic, colorimetric, microscopic, photographic, or visual signals of the one or more solid compounds at a position in the container before, at predetermined times during migration, and after migration.
In any one of the embodiments described herein, the method includes obtaining and processing microscopic or photographic images of the one or more solid compounds at a position in the container before, at predetermined times during migration, and after migration.
In any one of the embodiments described herein, the light intensity of one or more portions of the image before, at predetermined times during migration, and after migration is measured.
In any one of the embodiments described herein, the signals, images, or light intensity measurements of the container are processed by using dynamic time warping, barycenter averaging, machine learning, or a combination thereof.
In any one of the embodiments described herein, the machine learning includes deep neural networks.
In any one of the embodiments described herein, the machine learning includes supervised deep learning to train a convolutional neural network on hundreds-to-thousands of signals, images, or light intensity measurements.
In any one of the embodiments described herein, the analysis of unknown mixtures includes inputting one or more generated signals, images, or light intensity measurements into the trained convolutional neural network and obtaining an output of the identity of the mixture.
The invention is described with reference to the following figures, which are presented for the purpose of illustration only and are not intended to be limiting. In the Drawings:
Density can be useful to separate and characterize a wide range of materials. For example, a mixture of particles can be separated and identified based on their behavior in a uniform force gradient (e.g., viscous medium, centrifugal force, magnetic fields, and a combination thereof), which, in turn, is dependent upon their individual densities. Density can also be useful to separate, characterize, and identify both biological and non-biological materials. Density-based methods can be used to, for example, characterize materials, to separate, isolate, or fractionate sub-populations from complex mixtures, and to follow changes in density in systems (e.g., responses of biological cells to drug treatments, such as bacteria, and chemical reactions, such as polymerization).
Analytical methodologies—including simple centrifugation-based methods (e.g., Percoll gradient centrifugation) and more specialized techniques and types of instrumentation (e.g., methods based on pycnometers, density gradient columns, or vibrating tube densitometers)—are examples of the uses of density for analysis and separation. More complex approaches (e.g., microfluidics-based approaches using cantilever-based microresonators) are also expanding the uses of density.
Another technique that enables analysis and separation based on density is magneto-Archimedes levitation (also referred to as “magnetic levitation” or “MagLev”). Existing MagLev uses competing gravitational (buoyant) and magnetic forces to form an effectively continuous density gradient in an aqueous paramagnetic medium in a magnetic field. In some embodiments, a mixture of substances suspended, but not dissolved in, the aqueous paramagnetic medium separates into its component parts based on their densities in response to this gradient. In these embodiments, the existing configuration of MagLev-use of an aqueous paramagnetic medium-presents a challenge to separating or analyzing mixtures of substances in which one or more of its components are aqueous-soluble. Such mixtures include, but are not limited to, recreational drug compositions, pharmaceutical compositions, environmental samples, compositions from chemical manufacturers, compositions from manufacturers of polymers, and composition of food products or ingredients. To overcome this challenge, the inventors found that use of non-aqueous paramagnetic media including a paramagnetic metal complex soluble therein enables MagLev analysis of mixtures including aqueous-soluble substances.
MagLev SystemThe present invention is now described with reference to
In some embodiments, the magnetic levitation system is described by reference to
In some embodiments, the magnetic levitation system is described in
In some embodiments, the container is any closed or open vessel, and constructed of any material that is capable of holding the paramagnetic medium. Non-limiting examples of materials include glass, plastic, and a non-magnetic/non-paramagnetic metal. Non-limiting examples of the container include cuvettes, jars, test tubes, centrifuge tubes, and capillary tubes.
In some embodiments, the first and/or second magnets are permanent magnets. In some embodiments, the first and/or second magnets are neodymium (“NdFeB”) magnets. In some embodiments, the first and/or second magnets are samarium-cobalt (“SmCo”) magnets. In some embodiments, the first and/or second magnets are ferrite magnets consisting of iron(III) oxide blended with one or more additional elements, such as barium, manganese, nickel, and zinc. In some embodiments, the first and/or second magnets are Alnico magnets consisting of aluminum, nickel, and cobalt alloys. In some embodiments, the first and/or second magnets are electromagnets. In some embodiments, the first and/or second magnets are superconductive electromagnets.
In some embodiments, the first and/or second magnets are shaped as blocks, cylinders, spheres, discs, rings, or other geometrical shapes.
MagLev System in Non-Aqueous SolutionsIn certain embodiments, MagLev analysis of mixtures including aqueous-soluble substances are suspended in non-aqueous solution that include certain complexes.
In some embodiments, the complex has the structure M(-L)x, where M is a paramagnetic metal, each L is independently a same or different ligand that coordinates to the metal via electron donation, and x is an integer from 1-8. In some embodiments, the complex has the structure
In addition to the above complexes, any other combination of L1-L8 are contemplated.
In some embodiments, certain of L1-L8 may be joined together by covalent bonding to a substituent group consisting of 1-20 carbon atoms, forming one or more multi-dentate ligands. Non-limiting examples of complexes with multi-dentate ligands include
where the complex has a bi-dentate L1-L2 ligand, a tri-dentate L1-L3 ligand, a tetra-dentate L1-L4 ligand, a penta-dentate L1-L5 ligand, and a hexa-dentate L1-L6 ligand, respectively. The symbol
denotes the substituent group consisting of 1-20 carbon atoms. In addition to the structures shown above, any combination of mono- and multi-dentate ligands is contemplated.
Non-limiting examples of M include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, cerium, praseodymium, neodymium, europium, gadolinium, terbium, dysprosium, copper, holmium, erbium, thulium, and lanthanum.
In some embodiments, at least one of L1-L8 includes electron-donating elements, electron-donating groups including said electron-donating elements, or combinations thereof. Non-limiting examples of electron-donating elements include oxygen, nitrogen, sulfur, and the like. Non-limiting examples of electron-donating groups include oxazoles, imidazoles, phosphine oxides (e.g., trioctylphosphine oxide, tributylphosphine oxide, and triphenylphosphine oxide), pyridines, bipyridines, phenanthrolines, diketones, diketonates, diamines, carboxylates (e.g., 2-methylvalerate and ethylenediaminetetraacetic acid), and the like.
In some embodiments, MagLev is used to separate one or more components of a mixture based on density. In certain embodiments, MagLev is used to separate one or more components of a mixture that is dissolvable in an aqueous solvent based on density. In some embodiments, the mixture can be suspended in a non-aqueous paramagnetic medium. In these embodiments, when this mixture is placed in a non-aqueous paramagnetic solution between two or more magnets with their like-poles facing each other, the components of the mixture will occupy different positions in the paramagnetic solution according to their density. In some embodiments, by comparing the levitation height of a particular substance in a particular paramagnetic solution to, for example, a table or database of levitation heights of substances in that paramagnetic solution, the identity of the substance can be determined. In other embodiments, alternatively or additionally, the separated components can be isolated from the paramagnetic solution and subjected to further analysis.
In other embodiments, MagLev, unlike some of the methods discussed above, is, for example, applicable to a wide range of samples, is highly portable, is relatively inexpensive, and provides relatively fast separation. Therefore, MagLev may be useful for analysis of samples in a wide range of settings. Non-limiting examples of such settings can include academic and industrial research, development, and manufacturing, including in the pharmaceutical and materials science fields, environmental testing, such as testing for pollutants and other contaminants, and law enforcement, such as forensic analysis. In some embodiments, MagLev can be used for forensic analysis of powdered mixtures of illicit drugs, adulterants, and/or diluents. In some embodiments, the separated substances are also readily retrievable from the paramagnetic medium by, for example, pipet, which highlights the added advantage of MagLev for both separation and analysis of mixtures.
In some embodiments, the exemplary advantages of MagLev make it an attractive means for analyzing mixtures of illicit drugs by, for example, forensic analysts in field settings. Small (e.g., <50 mg) samples of mixtures can be challenging to separate or characterize (e.g., determine the identities of the components thereof) because of the relatively low concentration or weight percent of the components of the mixture. Large mixtures (e.g., >50 mg), too, can be challenging to separate or characterize where one or more components of the mixture are present in low concentration or weight percent (e.g., <10 wt %). Therefore, in some embodiments, MagLev can be particularly useful for separation and identification of the components present in a complex mixture at dilute concentrations or low weight percent, including, but not limited to, small samples of illicit drugs that are diluted by adulterants and other dilutants.
In some embodiments, identifying illicit drugs are challenging because existing conventional paramagnetic solutions useful for MagLev are aqueous, and most illicit drugs are water-soluble. Moreover, existing conventional paramagnetic complexes useful for MagLev are not soluble in non-aqueous solvents. Applicants have surprisingly found that these challenges can be overcome by using certain paramagnetic complexes that are soluble in non-aqueous solvents. In some embodiments, the paramagnetic complex includes a scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, cerium, praseodymium, neodymium, europium, gadolinium, terbium, dysprosium, copper, holmium, erbium, thulium, or lanthanum complexe, each including at least one phosphine oxide, carboxylate, or diketonate ligand. In some embodiments, the paramagnetic complex includes a gadolinium complex including at least one phosphine oxide, carboxylate, or diketonate ligand, each containing electron-donating elements (e.g., oxygen and nitrogen) or groups (e.g., oxazoles, imidazoles, phosphine oxides, pyridines, bipyridines, and phenanthrolines.
Certain Paramagnetic ComplexesIn certain embodiments, at least one of L1-L8 includes
where each occurrence R1 is independently H, (C1-C20)alkyl, (C2-C2M)alkenyl, (C2-C2M)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
In some embodiments, the paramagnetic complex has the structure
where n is an integer from 1-7 and where
denotes the group consisting of 1-20 carbon atoms.
In some embodiments,
are independently selected from the group consisting of 2,2′-dipyridyl, optionally substituted with one or more R1, 1,10-phenanthrenyl, optionally substituted with one or more R1, and
where each occurrence of R2 is independently H, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
As described herein, non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Non-limiting examples of alkenyl groups include ethenyl, allyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl,
2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. Non-limiting examples of alkynyl groups include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, and hex-3-ynyl. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
Non-limiting examples of aryls include phenyl, biphenyl and naphthyl. Non-limiting examples of heteroaryls include pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, oxazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzimidazolyl, benzofuryl, and the like.
In some embodiments, the paramagnetic complex has the structure,
is defined as above.
In some embodiments, the paramagnetic complex has the structure
where R1 and R2 are defined as above.
In some embodiments, each occurrence of R1 and R2 is independently (C1-C10)alkyl or (C6-C10)aryl. In some embodiments, each occurrence of R1 and R2 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, or isomers thereof. In some embodiments, each occurrence of R1 and R2 is independently methyl, butyl, tert-butyl, octyl, or phenyl.
In some embodiments, M is gadolinium.
In some embodiments, the paramagnetic complex is
In some embodiments, the paramagnetic complex is
In some embodiments, the solvent is a non-aqueous solvent. Non-limiting examples of non-aqueous solvents include acyclic and cyclic hydrocarbons, acyclic and cyclic halo- or per-halo hydrocarbons, aromatic hydrocarbons, acyclic and cyclic ethers, and acyclic and cyclic aldehydes, ketones, esters, and amides. In some embodiments, the solvent is pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, carbon tetrachloride, tetrachloroethylene, dichloromethane, trichloromethane, ethers (e.g., diethyl ether and tetrahydrofuran), and esters (e.g., ethyl acetate, and butyl acetate), including all isomers and a combinations thereof. In some embodiments, the solvent is hexane, tetrachloroethylene, or a combination thereof. In some embodiments, the solvent is tetrachloroethylene.
In some embodiments, the solvent is an aqueous or protic solvent. Non-limiting examples of aqueous or protic solvents include water, acyclic and cyclic alcohols, amines, thiols, carbonates, sulfoxides, and carboxylic acids.
Analytical Methods Using Position AnalysisIn another aspect, a method of analyzing a sample including one or more solid compounds is described, including:
(a) providing the magnetic levitation system of any one of the preceding embodiments;
(b) depositing the sample in the solution including the paramagnetic gadolinium complex; and
(c) allowing each of the solid compounds in the sample to migrate to a position in the container indicative of its density.
In some embodiments, the sample can be an amorphous, crystalline, or powdered sample. In some embodiments, the sample includes controlled substances, adulterants, and diluents that are found in pharmaceuticals and recreational drug products.
In some embodiments, the one or more solid compounds are present in the sample 108 at between 0.01 and 100 weight percent. In some embodiments, the one or more solid compounds are present in the sample at 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weight percent, or within a range of the weight percentage bounded by any two values described herein. In some embodiments, the one or more compounds are present in the sample between 0.01 and 10 weight percent.
Non-limiting examples of the one or more solid compounds in the sample are fentanyl, acetyl fentanyl, benzyl fentanyl, carfentanyl, cocaine, heroin, oxycodone, methamphetamine, cannabinoids, lysergic acid diethylamide, methaqualone, methadone, hydromorphone, Ritalin, Adderall, peyote, 3,4-methylenedioxymethamphetamine, acetaminophen, caffeine, diltiazem, dipyrone/metamizole, lidocaine, hydroxyzine, levamisole, papaverine, procaine, phenacetin, dimethyl sulfone, D-fructose, D-glucose, α-lactose, D-mannitol, sodium carbonate, starch, including potato starch, sucrose, talc, quinine, butylated hydroxytoluene, hypromellose, polyethylene glycol, polyethylene oxide, magnesium stearate, titanium dioxide and other colorants, and isomers and mixtures thereof. In some embodiments, the one or more solid compounds present in the sample include fentanyl-HCl and/or caffeine. In some embodiments, the one or more solid compounds, including those listed here, are present in the sample in free-base or salt form. Non-limiting examples of salt forms include sodium, aluminum, potassium, calcium, hydrochloride, citrate, nitrate, sulfate, acetate phosphate, diphosphate, maleate, mesylate, tartrate, and gluconate salts. In some embodiments, the salt is a hydrochloride salt.
In some embodiments, the method further includes
(d) analyzing one or more of the solid compounds to determine or confirm its identity
In some embodiments, the method of analyzing a sample including one or more solid compounds optionally includes positioning the sample container such that one or more of the levitated components contacts the wall of the container, followed by analyzing said component(s) through the wall of the container using a portable spectrometer. In some embodiments, the portable spectrometer includes a Raman spectrometer.
In some embodiments, the method of analyzing a sample including one or more solid compounds optionally includes isolating the one or more solid compounds from the paramagnetic solution after migration. In some embodiments, isolation is conducted by removing the one or more solid compounds using, for example, a pipette, a siphon, a spoon, a spatula, or a small basket.
In some embodiments, the one or more solid compounds are analyzed by other techniques after isolation from the paramagnetic solution 106. Non-limiting examples of such techniques include infrared spectroscopy, including Fourier transform infrared spectroscopy with attenuated total reflectance (“FTIR-ATR”), mass spectrometry, nuclear magnetic resonance spectroscopy (“NMR”), Raman spectroscopy, X-ray diffractometry, capillary electrophoresis, gas chromatography, ion-mobility spectrometry, liquid chromatography, microcrystalline tests, supercritical fluid chromatography, thin layer chromatography, ultraviolet/visible spectroscopy, macroscopic (visual) examination, colorimetric tests, fluorescence spectroscopy, immunoassays, melting point analysis, and pharmaceutical identifiers (package inserts). In some embodiments, the technique is FTIR-ATR. In some embodiments, the technique is Raman spectroscopy. In some embodiments the technique is mass spectrometry. In some embodiments, the technique is X-ray diffractometry. In some embodiments, the technique is a colorimetric test. In some embodiments, the technique uses a portable or handheld device.
In some embodiments, the method of analyzing a sample including one or more solid compounds further includes:
(e) generating a profile of the position of the one or more compounds relative to the container; and
(f) generating a database including a plurality of profiles, each of which corresponds to a known solid compound or a known mixture of solid compounds.
In some embodiments, the profile of the sample and the profiles of the database are determined at a plurality of time points after the sample is deposited in the solution in step (b).
In some embodiments, the MagLev device is described by
In some embodiments, the method of analyzing a sample including one or more solid compounds further includes:
(g) comparing the generated profile of the sample to the profiles in the database.
In some embodiments, step (g) further includes determining the particle size or the mixture of particle sizes of the one or more solid compounds.
In some embodiments, the step of comparing the generated profile of the sample to the profiles in the database includes determining and/or confirming the identity of the one or more solid compounds, or determining and/or confirming the source of the one or more solid compounds, or determining and/or confirming the particle size or the mixture of particle sizes of the one or more compounds, based on the comparison.
In some embodiments, the step of comparing the profile of the sample to the profiles in the database further includes using a computer to calculate the distances between the generated profile of the sample and the profiles in the database to identify a profile in the database within a minimum distance to the generated profile. Non-limiting examples of the distance are the Mahalanobis or Euclidian distances.
In some embodiments, dynamic time warping (“DTW”) is used to measure the similarity between profiles of the sample generated at a plurality of time points. In some embodiments, DTW is used to measure the similarity between profiles of the sample generated at a plurality of time points to profiles in the database generated at a plurality of time points. In some embodiments, the profiles of the sample and the profiles in the database are averaged and DTW used to measure the similarity between the average profile of the sample and the average profiles in the database.
In some embodiments, the profile consists of an image of the container. In some embodiments, DTW is used to compare the generated image of the container to images in the database. In some embodiments, images are recorded at a plurality of time points, optionally averaged, and DTW used to compare the generated images/average image to images/average images in the database. In some embodiments, the light intensity as a function of position in the container is measured to determine the profile. In these embodiments, the light intensity at a position of the container including only paramagnetic solution is different than the light intensity at a position of the container where one or more compounds is present. In some embodiments, DTW is used to compare the generated light intensity profile with the light intensity profiles in the database. In some embodiments, light intensity profiles are generated at a plurality of time points, optionally averaged, and DTW used to compare the generated light intensity profiles/average profile to the generated light intensity profiles/average profiles in the database.
In some embodiments, DTW finds point correspondences between generated and database profiles by warping them in the time domain. In some embodiments, DTW computes the set of point correspondences that minimizes the cumulative distance between the sequences.
In some embodiments, the averaging process is non-trivial when performed on variable-length signals. Therefore, in some embodiments, DTW barycenter averaging (“DBA”) was used to compute the average profile, including profiles consisting of images and light intensities, and the standard deviation. For example,
In some embodiments, an unknown mixed powder sample can be analyzed by calculating the similarity between the profile, optionally averaged over a plurality of time points, (i.e., position of the one or more compounds relative to the container) of an unknown sample and the profiles, optionally averaged over a plurality of time points, of known compounds or mixtures in the database. In some embodiments, the closest similarity between the unknown profile and a known profile in the database is used to identify the unknown mixture. As used herein, the similarity between the unknown profile and each known profile refers to the distance (e.g., Mahalanobis distance) as described above.
In some embodiments, if the similarity measurement does not reach a minimum distance, the event will be labelled as unknown. In some embodiments, the minimum distance (e.g., Mahalanobis distance), is a few (e.g., 10 s) standard deviations. Otherwise, in other embodiments, the unknown will be identified according to the greatest similarity.
In some embodiments, mixtures are detected that were previously identified and possess a database profile. In some embodiments, combinations of substances, such as, for example, lidocaine and caffeine, represent new representations. In some embodiments, this method may be especially useful for identification of samples that come from the same batch as a sample that has previously been classified, and to find samples that are of the same composition (i.e., same recipe), but not necessarily the same batch.
In some embodiments, the comparison between generated profiles and profiles in the database uses machine learning. In some embodiments, the machine learning includes deep neural networks, such as, for example, convolutional neural networks. In some embodiments, supervised deep learning, a subset of methods within machine learning, is used to identify known constellations of mixtures. In these embodiments, the convolutional neural network (“CNN”) is trained on hundreds-to-thousands of parameters, from datasets of labeled data (various mixtures of drugs) using cloud services, such as IBM Watson, since, in some embodiments, training of such networks can be computationally involved. In some embodiments, the analysis of unknown mixtures consists of inserting a new image into the trained neural network which will output the maximum-likelihood class. The CNN can be extended with any number of known mixtures; this approach requires, in some embodiments, large numbers of labeled data (e.g., images from mixtures of drugs in MagLev).
In yet another aspect, a kit is described, including:
a first and second magnets as described in any one of the previous embodiments;
a container as described in any one of the previous embodiments;
a paramagnetic gadolinium complex as described in any one of the previous embodiments, including at least one phosphine oxide ligand; and
instructions for assembling a magnetic levitation system as described in any one of the previous embodiments. In some embodiments, the kit further includes the solvent as described in any one of the previous embodiments. In some embodiments, the instructions for assembling a magnetic levitation system include placing the first and second magnets such that the surfaces of their like-poles are facing each other. In some embodiments, the instructions for assembling a magnetic levitation system further include placing a container the first and second magnets' like poles. In some embodiments, the instructions for assembling a magnetic levitation system further include adding, to the container, a solution including the paramagnetic gadolinium complex in the solvent as described in any of the embodiments disclosed herein. In some embodiments, the instructions for assembling a magnetic levitation system further include depositing a sample including one or more solid compounds in the solution including the paramagnetic gadolinium complex; and allowing each of the solid compounds in the sample to migrate to a position in the container indicative of its density.
EXAMPLES Example 1: MagLev TheoryIn some embodiments, a diamagnetic object (e.g., a crystal or a particle from a mixture of powdered drugs) achieves a stable levitation height in a paramagnetic solution in an applied magnetic field (e.g., a linear field gradient) when the magnetic force, {right arrow over (F)}mag, the object experiences (as a result of the interaction between the paramagnetic suspending solution and the applied magnetic field) counterbalances its gravitational force, {right arrow over (F)}g, (corrected for the effect of buoyancy; see
In some embodiments, ρ (g cm−3) is the density of the sample, ρmedium (g cm−3) is the density of the paramagnetic solution, χ (unitless) is the magnetic susceptibility of the sample, χmedium (unitless) is the magnetic susceptibility of the paramagnetic solution, g (9.8 m s−2) is the constant of gravitational acceleration, μo (4π×10−7 N·A−2) is the magnetic permeability of the free space, Bo(T) is the strength of the magnetic field at the center of the top surface of the bottom magnets, and d (m) is the distance of separation between the two like-poles-facing magnets.
a sample particle (modeled using a cubic crystal having a side of 100 μm) experiences when suspended in a paramagnetic solution (0.5 M Gd(DPM)3TOPO) and placed in the magnetic field shown in
The MagLev device dimensions and weight were 205×45×45 mm and 700 g, respectively). The MagLev device consisted of two NdFeB magnets (Neodymium Magnets N42 Block; dimensions: 25.4×25.4×50.8 mm; appliedmagnets.com), with like-poles facing each other, with a 25.5 mm face-to-face separation resulting in a 0.51 T magnetic field (as measured with a DC gauss-meter; model GM1-ST; AlphaLab, Inc.) at the surface of the magnets (see
Tris(dipivaloylmethanato) gadolinium(III) (Gd(DPM)3; 2.0 g, 2.7 mmol; Alfa Aesar) was suspended in hexanes or n-heptane (20 mL; 10 mL per g of starting material) at room temperature. Trioctylphosphine oxide (TOPO; 1.0 g, 2.7 mmol; Sigma-Aldrich) was added to form a colorless suspension, which became a clear solution within 10-30 minutes (depending on batch size). The solution was stirred at room temperature (22° C.) for approximately 18 hours. The solvent was removed on a rotary evaporator (60° C. bath temperature) at reduced pressure (first at 100-25 mbar, then at 10-3 mbar) to obtain the Gd(DPM)3TOPO complex as a pale yellow, viscous oil (2.88 g, 2.67 mmol) with a density of approximately 1.1 g/cm3. This synthesis was successfully performed starting with 1-30 g of Gd(DPM)3. The yellow color intensified with larger scales and higher concentrations. The compound was characterized with Fourier transform infrared attenuated total reflectance (“FTIR-ATR”) spectroscopy (see
FTIR-ATR (Bruker Platinum) spectra of Gd(DPM)3TOPO (900 mM) and Gd(acac)3TOPO (1100 mM in tetrachloroethylene) were recorded by placing a drop of chelate on the ATR diamond window (air set as blank). The spectrum of tetrachlorochloroethylene was measured as a control (air set as blank). Spectra were recorded from 4000-400 cm−1 at a resolution of 1 cm−1 with 64 sample and background scans (see
The compound was stable for more than one month at 22° C. in a capped and air-tight bottle when stored at room temperature in ambient air. In some cases, precipitation occurred after extended storage. The precipitate made the Gd(DPM)3TOPO oil appear opaque and, in some embodiments, can be removed by diluting the compound with hexane to 450 mM and filtering the solution through polyether sulfone syringe filters (0.2 μm, Thermo Fisher Scientific, Inc.).
Example 4: Synthesis of the Gd(acac)3TOPO-Chelate ComplexGadolinium(III) acetylacetonate (Gd(acac)3; 2.3 g, 5.0 mmol) was added to a 50 mL round-bottomed flask attached to a vacuum outlet and TOPO (2.0 g, 5.2 mmol) was added as a powder. The temperature of this solid mixture was slowly raised to 100° C. and kept constant for five minutes. The TOPO melted and solubilized the Gd(acac)3. Heating was stopped and a vacuum (150 mbar) was applied for 2 minutes. In some embodiments, heating for longer periods led to significant darkening of the solution and formation of insoluble precipitates (e.g., inorganic polymers). Also, in some embodiments, rapid heating led to overheating, and hence, in these embodiments, the heating step was conducted slowly (over approximately 5 minutes). This mixture was cooled to 30-40° C. and 1,2-dichloroethylene (4.5 mL) was added. The solution looked turbid. The small amount of insoluble precipitate was removed by filtration using a polysulfone syringe filter (0.4 μm pore size). In some cases, filter paper did not work, as pressure was required to filter the relatively viscous solution. This solution was cooled to room temperature to give a faint yellow solution with a density of approximately 1.3 g/cm3. Treatment with active charcoal did not lead to significant improvement in the color of the solution. The compound was characterized with FTTR-ATR (see
Gadolinium(III) diethylenetriamine triacetic acid didecyldiacetamide, C11-DTTA, molecular weight 1107 g mol−1) was also synthesized. This compound is a hexadentate chelate with at least two free coordination sites on gadolinium(III), which may be occupied by water. In the absence of stronger ligands, this complex dissolved in the organic solvents at concentrations up to approximately 0.4 M. However, in some cases, above a concentration of 0.2 M, the increased viscosity of the solutions (higher viscosity than glycerol) impeded the separation of particles, and, in these cases, caused a large increase in the time required for separation with MagLev.
Example 5: Determination of Magnetic Susceptibility for the Paramagnetic ComplexesThe magnetic susceptibilities of the gadolinium chelate complexes were determined using the Evans method. In some embodiments, the magnetic susceptibilities for small molecules can be calculated from experimental data using Equation 2:
where χc is the magnetic susceptibility (m3 mol−1) of the compound, Δf is the observed difference in chemical shift in 1H-NMR (Hz), F the frequency of the NMR spectrometer (Hz), and c is the concentration (mol m−3) of the paramagnetic substance.
The differences in chemical shifts (Δf) that were caused by the paramagnetic complexes were recorded using 1H NMR (see
The Gd(DPM)3TOPO was obtained from the synthesis shown in Example 3 as a viscous oil, which was fully soluble in hexane, heptane, octane, decane, and tetrachloroethylene within the range of concentrations tested (34-900 mM). The compound was soluble in other non-polar organic solvents as well—e.g., carbon tetrachloride and cyclohexane. Solutions based on these solvents were all able to levitate powders (see, e.g.,
The combination of hexane and tetrachloroethylene as solvents for the paramagnetic solutions were chosen because of their large difference in density (0.65 versus 1.62 g cm−3). This difference allowed for adjustment of the density of the paramagnetic solution by changing the proportion of the solvents. A halogenated solvent was chosen because it is a non-polar organic solvent that has sufficiently high density (>1.5 g cm−3). Both solvents are non-polar and are fully miscible with each other, and were also fully miscible with the two types of non-polar gadolinium complexes (i.e., Gd(DPM)3TOPO and Gd(acac)3TOPO) used. There were other beneficial properties of theses solvents: (i) They have boiling points that are significantly higher than room temperature (e.g., n-hexane: 69° C. (other suitable n-alkanes was explored, see
The toxicities of the solvents used in the paramagnetic solution were acceptable if handled with the correct safety procedures. The U.S. Hazardous Materials Identification System (“HMIS”) ranks hexane as a “moderate hazard”, and tetrachloroethylene as a “serious health hazard” for human health (the scale ranges from “minimum hazard” to “severe hazard”).
Hexane is a flammable solvent used in, for example, glues, food-oil extraction, and chromatography. Inhalation of hexane in air for short periods of time can cause mild effects on the central nervous system, including, for example, dizziness, giddiness, slight nausea, and headache. Longer time periods of exposure (e.g., inhalation or contact) to hexane is associated with effects on the nervous system, for example, nerve damage in humans.
Tetrachloroethylene is a nonflammable solvent that is used, for example, as a solvent in commercial dry-cleaning. The effect of chronic exposure to tetrachloroethylene can be severe, and the solvent is a suspected carcinogen. Precautions should be taken to avoid inhaling the fumes of the tetrachloroethylene and to avoid absorption the solvent through the skin. Tetrachloroethylene and carbon tetrachloride both are rated (HMIS) as “severe hazards” to human health, however, carbon tetrachloride is a more potent liver toxin.
In some embodiments, precaution should be taken to reduce the amount of evaporation of solvent from the paramagnetic solution. In some embodiments, the faster evaporation of the low-density hexane solvent relative to the high-density tetrachloroethylene solvent and the gadolinium chelate complexes can result in an increase in the density of the paramagnetic solution. In some embodiments, the change in density can interfere with the density calibration of the MagLev device. In some embodiments, the evaporation of the solvents can be minimized by reducing the time of the separation and by covering the top of the cuvette with aluminum foil. In some embodiments, the hexane can also be replaced with solvents with a higher boiling point, such as heptane (98° C.), octane (125° C.), nonane (151° C., or decane (174° C.) to reduce the rate of evaporation of the solvent. For examples of separation of powders using MagLev with different n-alkanes, see
Images were edited using Adobe Lightroom. The white balance was manually set, selecting a spot in the darkest and brightest areas of the image for the calibration of the extremes, respectively. Edits were performed uniformly over the entire area shown in the figures, and with identical settings for every image of the series in
All illicit drugs were produced internally by the Drug Enforcement Administration (“DEA”) for use as reference materials, except for the heroin-HCl, which came from a seized sample of South American origin. All experiments with illicit drugs were performed at facilities associated with the DEA. All adulterants and diluents were procured from Sigma-Aldrich, except the following: diltiazem hydrochloride (from EMD Millipore), D-mannitol (from Lancaster Synthesis, Inc.), papaverine.HCl (from ICN Biomedicals), and sucrose (from EMP Millipore).
Disposable UV-grade methacrylate cuvettes (product no. Z188018, Sigma Aldrich, outer dimensions 12.7×12.7×45 mm, inner dimensions: 10×10×45 mm) were cut with a band saw to a height of 25 mm (approximately 2.5 mL capacity) to fit between the faces of the two magnets. This particular type of plastic cuvette showed good resistance to repeated exposures to the non-polar paramagnetic solutions used. The density gradient was mapped to obtain a standard curve, by recording the height of the levitating glass bead density standards (American Density Materials, Inc.) of known densities, with a ruler for reference of distance (see
The time of separation for the powders depended mainly on the following five reasons: (i) The sample size, because large amounts of powder took longer to separate than small samples. (ii) The particle size, because small particles took longer time to separate than large ones. (iii) The concentration of gadolinium(III) in the paramagnetic solution, because a higher concentration of Gd3+ resulted in faster separation. (iv) The viscosity of the paramagnetic solution, because an increase in viscous drag on the particles resulted in slower separation. (v) The magnetic field strength, because higher magnetic field strength resulted in faster separation.
A custom larger cuvette was made (see
Powders of compounds of larger particle size (e.g., fentanyl, acetyl-fentanyl, benzyl fentanyl, and heroin) reached their equilibrium positions in the paramagnetic solution faster than compounds of smaller particle size. Compounds present as small particles (e.g., cocaine, methamphetamine, and lactose) moved more slowly in the paramagnetic solution (consistent with Stoke's law).
All experiments with active compounds were performed at a DEA facility that had the necessary approvals and infrastructure for handling of such compounds. Active compounds were associated with significant legal oversight, permits, safety precautions, and limits on the type and amount of compound that can be procured. The bulk of the method development of the MagLev separation took place at Harvard University, which does not have approval to work with schedule I and II drugs.
To facilitate the development of the methodology and the investigation of the dynamics of the separation in the MagLev device, a model system was developed that does not contain controlled compounds. The model system consisted of a binary mixture of two compounds, lidocaine.HCl and caffeine, both of which are minimally regulated (along with additional benefits) compared to active compounds (chemistry laboratories can buy them without special approval). This model system was chosen for the following reasons: (i) The two compounds were water-soluble and, thus, they mimicked many active compounds; (ii) hydrochlorides, such as lidocaine.HCl, were the common salt forms found in seized mixtures of powdered illicit drugs; (iii) both compounds were commonly found as adulterants in powdered mixtures of illicit drugs; (iv) laboratories could procure them without special permits and documentation; (v) they had distinctly different densities; (vi) their particle sizes were different when observed by eye; (vii) they were inexpensive (Sigma Aldrich: lidocaine.HCl, Prod. #: PHR1257-500MG, $127 per gram; caffeine, Prod. #: C0750-5G, $4 per gram); and (viii) their toxicity was acceptable; i.e., a dust mask was sufficient protection to avoid inhalation of particles when the dried powders were handled (which is important in the case of lidocaine.HCl).
Example 13: Scanning Electron Microscopy Imaging of PowdersTo obtain SEM images (see
A mixture of lidocaine.HCl and caffeine (50:50 wt %) was levitated in the MagLev device until the powders reached their equilibrium levitation heights. The powders were carefully extracted from the cuvette using Pasteur pipettes (guided by pivoting of the hand) and collected by suction filtration on a grade 3 Whatman filter paper. The residue was washed three times with 40 mL portions of solvent (hexane), air-dried, and gently scraped off the filter paper with a spatula and stored in an air-tight glass vial (e.g., up to five days) until characterized. For 1H NMR, 3 mg of the residue was dissolved in 0.6 mL of DMSO-d6 and transferred to a NMR tube for NMR analysis. 1H NMR spectra (see
The powdered samples that contained powdered lidocaine.HCl and caffeine (same washing procedure as for the 1H-NMR analysis) were analyzed in their dry, powdered state with FTIR (see
MagLev enabled the separation of powdered mixtures of illicit drugs (e.g., cocaine, methamphetamine, heroin, fentanyl and its analogs), adulterants, and diluents based on density, and allowed the presumptive identification of individual components. In some embodiments, small samples (mass <50 mg), with low weight percentages of illicit drugs, present a particular challenge to analysis for forensic chemists. The MagLev device—a cuvette containing a solution of paramagnetic gadolinium(III) chelate in a non-polar solvent, placed between two like-poles-facing NdFeB magnets—allowed separation of seven relevant compounds simultaneously. In particular, initial separation with MagLev, followed by characterization by FTTR-ATR, enabled identification of fentanyl in a sample of fentanyl-laced heroin (1.3 wt % fentanyl, 2.6 wt % heroin, and 96.1 wt % lactose). MagLev allowed identification of unknown powders in mixtures and enabled confirmatory identification based on structure-specific techniques.
The abuse of drugs is a major public health problem, with fatalities attributed to overdoses numbering 7,600 in the E.U. (78% involving opioids) and 70,000 in the U.S. (86% opioids) in 2017. A potent subgroup of these compounds are the synthetic opioids (mainly fentanyl and its analogs) that were involved in 30,000 deaths in the U.S. In some embodiments, “opioids” are defined as molecules that interact with the opioid receptors in neural and intestinal cells. In some embodiments, “opiates” are opioids of natural or semi-natural origin.
Fentanyl—a painkiller and anesthetic that is widely used in medicine—has particular relevance in law enforcement because it is the predominant synthetic opioid found in seized samples of drugs of abuse. Fentanyl and its analogs can be orders of magnitude more potent than natural opioids; for example, the activities of these compounds in suppression of pain, relative to morphine, are: morphine (potency≡1×), oxycodone (1.8×), acetyl fentanyl (16×), fentanyl (100×), and carfentanyl, (10,000×). These compounds are mainly used as additives in products that are marketed recreational, or “street”, drugs, such as, for example, “heroin” and “cocaine”. An addict may typically use 0.3-1.0 mg of fentanyl to achieve a high; a dose of 2.0-5.0 mg may cause death. In the U.S. (2017), the DEA found that the average content of fentanyl in drugs obtained from street-level retail was 5.1 wt % (with a total range of 0.1-97.8 wt % for all confiscated drugs). Fentanyl hydrochloride is a prominent fentanyl salt in seized samples, while the citrate salt is found in a minority of confiscated drugs.
To moderate potency, and to increase profit margins, drugs are commonly diluted with adulterants, i.e., semi-active compounds that are added to enhance the effect of the drugs or simply mimic their properties. For example, because drug users test the bitterness of mixtures to judge the content of heroin, acetaminophen and caffeine are added to maintain the bitterness of the mixture when heroin—which is bitter—is diluted. Diluents (non-active compounds, such as lactose, dimethyl sulfone, and glucose) are added to lower the concentration of the drug, and to make it easier to handle and use.
To identify a drug according to forensic standards of analysis, two to three different analytical methods can be used. Techniques with molecular specificity—X-ray diffractometry and IR, NMR, Raman, and mass spectrometry—are given the highest ranking. GC-MS is the workhorse in modern forensic drug laboratories (e.g., in most U.S. federal, state, and municipal laboratories—depending on the state), but the cost, the lack of portable systems, and the technical skill needed to handle this instrument prohibit large-scale use in the field. Most separations (capillary electrophoresis, gas chromatography, liquid chromatography, and other less-molecularly-specific techniques) are considered intermediate in value for identification. Other methods that provide more limited information about the molecular structure are in the third, lowest, category. When an appropriate combination of methods is used to confirm the presence of a compound (e.g., at least two techniques, with one from category A and the second from categories A, B, or C, or, alternatively, three techniques if at least two are from category B and the additional technique is from B or C), and when the sampling procedure adheres to defined protocols, the presence of the compound can be considered to have been identified. This level of identification is referred to as “confirmatory identification.”
In some embodiments, in the U.S., in confirmatory identification can only be performed by an expert (e.g., a forensic chemist). In some instances, a police officer cannot be admitted as an expert witnesses in court for chemistry or forensics and, therefore, the “opinion” of the police officer cannot be entered as fact. Thus, a measurement performed by a law enforcement officer with a confirmatory technique is assigned a standing similar to that of a presumptive technique. However, the use of techniques of high molecular specificity by law enforcement officers have the benefit of reducing the number of false positive and negatives that are inherent to most other presumptive identification techniques.
In some embodiments, MagLev has the potential to be used for presumptive identification, based on compound density. In some embodiments, presumptive identification is the lowest level of specificity (Category C in Table 5), but encompasses the most common group of analytical methods used to screen compounds in the field (outside of an analytical laboratory). Immunoassays and colorimetric tests are other examples; these techniques provide weak evidence of molecular identity, but are easily used in resource-limited circumstances (e.g., border inspection stations and mail-sorting facilities). MagLev has, however, the potential to enable more specific techniques because of its ability to separate dilute compounds in mixtures of powders. In some embodiments, MagLev has the potential to be used by forensic organizations for analysis of seized illicit drugs.
MagLev was used to determine three characteristics of a powdered sample: (i) the minimum number of compounds present in the sample, (ii) the densities of these separately levitating compounds (or mixtures of overlapping compounds) (see
In some embodiments, determining the composition of illicit drugs in the field faces at least four hurdles: (i) the technical and procedural training required to ensure correct handling of the sample, (ii) access to appropriate instruments, (iii) the risk of exposure to the drugs, and (iv) the highly variable composition of the drug mixtures. For these and other reasons, seized samples are often not analyzed for their constituents in the field, but only later at a local law enforcement facility, or at a well-equipped and competently staffed central laboratory. Shipping to, and analysis in, central laboratories can introduce long delays in the identification of molecular constituents of mixtures of drugs (e.g., backlogs in analysis are common).
In some embodiments, mixtures of illicit drugs can contain a wide range of compounds. With this in mind, separation of active compounds (with a range of chemical properties) commonly found in samples seized by law enforcement was conducted, including the hydrochloride salts of fentanyl, acetyl fentanyl, cocaine, heroin, and methamphetamine (see
In some embodiments, the synthetic opioids can be especially challenging to detect due to their high potency, which enables (and requires) high dilution (≤5 wt %) of the active components and, thus, makes the analyses of these opioids in small samples (≤50 mg) particularly difficult. For example, a fentanyl compound may be present only as a few crystals in a 50 mg sample.
Existing portable methods for detection of fentanyl include colorimetric tests, microcrystalline tests, electrochemistry, immunochemistry, near-infrared spectroscopy, surface-enhanced Raman spectroscopy, Raman spectroscopy, and FTIR spectroscopy. Common portable methods currently used in the field by law enforcement personnel for general detection of drugs are colorimetric tests, handheld Raman (e.g., Thermo Scientific TruNarc or Chemring Detection Systems PGR-1064), and FTIR (e.g., Thermo Scientific TruDefender FTXi and Smiths Detection HazMatTD Elite). Both Raman and FTIR-ATR (which are considered more sensitive and accurate than colorimetric tests) have limits-of-detection of approximately 5 wt %, and are therefore not sensitive enough to detect dilute drugs directly in the mixtures of illicit drugs, adulterants, and diluents.
MagLev was used to separate, and to measure the density and abundance of, compounds in mixtures of powdered illicit drugs (e.g., fentanyl, heroin, cocaine, and methamphetamine hydrochlorides), together with adulterants and diluents. This analysis focused on the psychoactive components in these mixtures of drugs (i.e., the “active” compounds). Fentanyl and its analogs were of particular interest, for which MagLev was used as a technique that both provides presumptive (i.e., tentative) identification of the compounds (based on density) and facilitates subsequent identification by other techniques. Combining MagLev (to separate mixtures, and to allow presumptive identification) and molecular spectroscopy (using whichever technique is most appropriate) for molecular identification provided a method of confirming the identity of drugs in mixtures (see
MagLev was used to separate dilute (1.0-2.6 wt %) compounds from powdered mixtures, including: (i) 1.3 wt % fentanyl-HCl, 2.6 wt % heroin-HCl, and 96.1 wt % α-lactose (see
The separation of lidocaine.HCl from caffeine (see
This model system facilitated the development of MagLev for uses with powdered mixtures of illicit drugs, and also for the investigation of the dynamics of separation of particulates in a MagLev device. MagLev separated the binary mixtures of lidocaine.HCl and caffeine of seven different compositions into two fractions, and the amount of compounds in each fraction (quantified by image analysis, see
MagLev separated crystals of both compounds within approximately 20 minutes, but some non-aggregated (small) particulates of caffeine remained suspended after this period (observed as less transparent paramagnetic solutions in samples of high (≥75 wt %) caffeine content), due to the high ratio of drag-to-magnetic-force for small particles. The time of separation of the illicit drugs (see
Following separation using MagLev, the fractions were extracted and characterized by NMR (see
MagLev was used to measure the densities of 23 compounds (6 active compounds, 10 representative adulterants, and 9 diluents) found in mixtures of powdered drugs (see
In some embodiments, MagLev are performed on suspended objects or particles. Most illicit drugs, adulterants, and diluents are readily water-soluble (with the notable exceptions of cocaine, phencyclidine, and heroin in their free-base forms). Thus, in some embodiments, their separation and analysis with MagLev requires non-polar paramagnetic solutions to suspend and levitate them. Few existing paramagnetic chelates are soluble at high concentration in non-polar solvents, while still maintaining a low viscosity of the solution. Therefore, in some embodiments, mixtures of hexane (ρ=0.66 g cm−3) and tetrachloroethylene (ρ=1.62 g cm−3) were used as the solvent for the gadolinium(III) chelate complexes, because mixtures of these solvents spanned the range of densities useful for analysis of powdered drugs, and had suitable characteristics (e.g., low polarity, appropriate density, low viscosity, and toxicity). None of the compounds (illicit drugs, adulterants, or diluents) investigated in these Examples (see Table 3) dissolved in the non-polar paramagnetic solutions used, as judged by eye (see
Using MagLev, it was possible to carry out presumptive identification of multiple compounds simultaneously (see
For powdered mixtures of illicit drugs, in some embodiments, a mixture of 5-12 compounds in one sample is not uncommon.
The densities of compounds determined by MagLev largely agreed with values reported in the literature (see Table 6), which were measured by, for example, XRD and calculated from the dimensions and occupancy of the unit cells, or by gas pycnometry. The density measurements deviated from literature values by less than 20.2%. The largest differences were recorded for the hydrochlorides of methamphetamine (20.1%), levamisole (10.7%), procaine (6.0%), cocaine (5.6%), and diltiazem (4.8%). Without wishing to be bound by theory, these differences may be due to impurities or different forms of the drug present in samples (e.g., as hydrates, solvates, or carbonates, admixture with other compounds with similar density, particles that are partly amorphous instead of fully crystalline, crystals that included polymorphs, or other issues). Nonetheless, these differences in density were largely irrelevant for separations, as long as the compounds do separate. In some embodiments, the values of densities for relevant compounds can, however, be important for the presumptive identification of compounds that have not been previously separated by MagLev, and should be better established (both in pure samples, and as encountered in different mixtures of illicit drugs).
To minimize errors, for compounds that have been previously characterized and that have been documented in look-up tables, density-based presumptive identification with MagLev can be performed under the same set of conditions (e.g., type of MagLev device, type of paramagnetic chelate complex, and concentration of solution) used for previous characterizations.
In some embodiments, MagLev is simple to use and portable. It thus, in some embodiments, offers a new method for screening drugs outside of a well-equipped forensic laboratory (e.g., at crime scenes and law enforcement sites). Because, in some embodiments, separation by MagLev is rapid, it could shorten the time required for presumptive identification of illicit drugs at crime scenes. In some embodiments, complementary and more precise techniques could subsequently be used for confirmatory identification, because MagLev is non-destructive. In some embodiments, the synergy of MagLev with FTIR-ATR is attractive for analysis of drugs because both techniques are portable, require little training to use, and work well with powdered compounds. In some embodiments, the two are also complementary because MagLev compensates for the low sensitivity of FTIR-ATR in complex mixtures, by separating and concentrating fentanyl or other compounds of primary interest. In some embodiments, uses of MagLev in this type of application can be optimized in the laboratory using easily obtained compounds—e.g., lidocaine.HCl and caffeine—that are relevant to illicit mixtures of drugs, as components of model systems, and can thus avoid the often prohibitive regulations placed on the use of most active compounds (see Table 4).
In some embodiments, producers of illicit drugs make new analogs more quickly than these compounds can be “scheduled” as illegal compounds. Before a drug can be scheduled, multiple agencies must determine if it has a “strong index of suspicion.” For example, for synthetic opioids, there must be a strong suspicion that the drug causes miosis, depressed respiration, changes in mental status, and additional signs of opioid toxicity. In some embodiments, a strength of MagLev is that the method is non-specific to the molecular structure or the biological activity; an additional, more structure-specific technique (e.g., FTIR or, Raman-spectroscopy, or mass-spectrometry) may be required to enable the assignment of new compounds to a class. In some embodiments, this characteristic also makes MagLev suitable for providing a rapid early warning of a new or unfamiliar compound whose density (and probably structure) varies only slightly from those of compounds of a previously known class of compounds (new analogs of fentanyl are an example); through separation, MagLev enables the molecular characterization of those compounds by other techniques. In some embodiments, MagLev could aid in the detection of new designer drugs, unconventional mixtures of drugs, fentanyl-laced drugs of inconsistent and unexpectedly high concentration, and harmful adulterants on the illegal market. Circumventing detection by MagLev would require additional and unfamiliar efforts on the part of providers of street drugs. In some embodiments, MagLev enables the characterization of dilute compounds in mixtures of powders using techniques that would otherwise not be able to identify the molecular structure of dilute compounds in mixtures of powders.
Example 17: Two Methods for Fingerprinting Powdered Mixtures of Drugs after Levitation with MagLevIn some embodiments, MagLev separation coupled with time-lapse photography, image analysis, and machine learning (including signal processing techniques) provides a method to obtain unique “fingerprints” of mixtures of powdered drugs of prescription or illicit origin. The separation of drug particles from mixtures were performed in a cuvette filled with an apolar paramagnetic solution (such that the dissolution of hydrophilic compounds was avoided or significantly reduced) that is placed between two permanent magnets held in position by a frame. The individual components of the mixtures equilibrated (levitated) at their equivalent density (corresponding to a specific position between the magnets—a ruler was placed next to the cuvette for reference) in the density gradient generated between the magnets, forming levitating “clouds” of particles of a more or less spherical shape. The n-position was defined as the middle of the centroid of the levitating clouds. Three different methods were used to generate the fingerprints:
-
- The first method of fingerprinting was based on the measurement of density and the amount of substance, and on modelling (see Method 1 below) the particle size distribution (taking into account the change in size of the clouds over time, the shape of the cuvette, and viscosity of the paramagnetic solution). This method relied on both the dynamic separation process (to determine characteristic particle sizes) and the final state of rest of the separated particles (to determine the density of the drugs).
- The second method (see Method 2 below) of fingerprinting was based on time series classification using signal processing, and machine learning. A classification method that used supervised learning to create representations of each powdered mixture was employed. When a new series of measurements was obtained, the measurements were compared to the stored class representations to determine the maximum likelihood classification. In some embodiments, the classification procedure built on several component techniques from the field of signal processing, for example, dynamic time warping (DTW) and DTW barycenter averaging (DBA).
- The third method (see Method 3 below) used machine learning, including deep neural networks, specifically, convolutional neural networks, for image classification.
In some embodiments, digital fingerprinting can be used to perform attribution, i.e., the process of finding the source of the powdered mixtures (e.g., illicit drugs), or the source of the components in the mixtures. To perform attribution with digital fingerprints, they are, in some embodiments, compared to other fingerprints in a database and the degree of similarity between the different fingerprints are estimated through different types of methods that compare different characteristics of the fingerprint. These methods, in some embodiments, can process and evaluate data about the types of drugs present, quantities of drugs relative to each other, and characteristic particle sizes of each drug. The fingerprints, in some embodiments, can be coupled to other types of data, such as time of seizure and location, enabling the tracking of similar types of fingerprints geographically and over time. This could, for example, be useful to track drug traffic networks to identify the batch, supplier, and, ultimately, the network of distribution channels in the drug trade. The methods described in this Example focus on the analysis of mixtures of powders that contain drugs. However, the method can be used on any powdered mixture (e.g., powdered chemicals, food products, or explosives).
Method 1In some embodiments, an experiment generates a series of approximately 100 images, or more, in a time series from a DSLR camera to be processed and analyzed. Each image was processed by first cropping the region of interest (bounded by the lower and side walls of the cuvette and the fluid meniscus at the top), extracting the “intensity,” i.e., the value channel in hue, saturation, value (“HSV”) color space, calibrating the number of pixels to a linear distance based on a ruler included in the image, and recording the timestamp of the image. After this processing step, each image was an n-by-m matrix of intensity values with known linear spacing (meters) and known time of image capture, where n and m are the height and width of the cropped image in pixels, respectively.
Following the processing step, each processed image was analyzed to characterize the location of suspended particles, as indicated by pixels with high intensity values due to particles reflecting light. To perform this analysis, the lateral pixels (in the m-direction) were averaged over each row in the matrix representing the image to yield a single value for each vertical pixel location within the image, resulting in an n-by-1 matrix representing the average amount of particles stored at each vertical location (height above the bottom magnet) within the MagLev device (see
In some embodiments, small clouds (a few crystals) of levitating compounds can, in some cases, be difficult to detect when averaging the intensity of the pixels for each m-row, especially if there is significant background noise. In some embodiments, an alternative method of generating intensity profiles over the n-direction is to map the light intensity along the m-position with maximum integrated area under the intensity curve (n versus m). In some embodiments, this method was not used to estimate the amount of substance but, using the intensity curve with the strongest possible signal, was used to detect the presence and position (density) of small clouds of compound. This latter method was used, as demonstrated in
In some cases, the images were taken with a set polarizers that were oriented perpendicular to each other, with the first polarizer being placed between the light source and the cuvette, and the second polarizer between the cuvette and the lens of the camera. The polarizers enabled identification of compounds that polarized light, adding another dimension to the fingerprint.
The time series (i.e., the averaged light intensity for each n-row of pixels inside the cuvette) was extracted, using the methods illustrated in
Several pathways within machine learning were investigated, including deep neural networks, specifically, convolutional neural networks, for image classification. Rather than processing the images and converting them to spatial sequences, entire sets of images were inserted to train the classifiers (one classifier for each mixture of powders).
Claims
1. A magnetic levitation system comprising:
- a first and second magnets having surfaces of their like-poles facing each other; and
- a container disposed between the first and second magnets' like poles and containing a solution comprising a paramagnetic complex in a non-aqueous solvent; wherein the paramagnetic complex comprises a paramagnetic metal and at least one ligand that coordinates to the paramagnetic metal via electron donation.
2. The system of claim 1, wherein the paramagnetic complex has the structure wherein M is a paramagnetic metal and L1, L2, L3, L4, L5, L6, L7, and L8 are ligands that coordinate to the paramagnetic metal via electron donation.
3. The system of claim 2, wherein L1, L2, L3, L4, L5, L6, L7, and L8 are independently selected from the group consisting of substituted or unsubstituted phosphine oxides, oxazoles, imidazoles, pyridines, diamines, bipyridines, phenanthrolines, diketonates, malonamides, malonates, β-ketoesters, β-ketoamides, carboxylates, dicarboxylates, and ethylenediaminetetraacetic acid.
4. The system of claim 2, wherein two or more of L1, L2, L3, L4, L5, L6, L7, and L8 are covalently bonded to a substituent group consisting of 1-20 carbon atoms.
5. The system of claim 2, wherein at least one of L1, L2, L3, L4, L5, L6, L7, and L8 comprises wherein each occurrence R1 is independently H, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
6. The system of claim 2, wherein the paramagnetic complex has the structure wherein n is an integer from 1-7 and wherein denotes the group consisting of 1-20 carbon atoms.
7. The system of claim 6, wherein are independently selected from the group consisting of 2,2′-dipyridyl, optionally substituted with one or more R1, 1,10-phenanthrenyl, optionally substituted with one or more R1, and wherein each occurrence of R2 is independently H, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl, (C3-C10)cycloalkyl, (C6-C10)aryl, or (C6-C10)heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, Ra, ORa, NRaRb, CORa, CO2Ra, or CONRaRb; and where Ra and Rb are independently selected from the group consisting of hydrogen and (C1-C6)alkyl.
8. The system of claim 2, wherein the paramagnetic complex has the structure,
9. The system of claim 8, wherein the paramagnetic complex has the structure
10. The system of claim 5, wherein each occurrence of R1 and R2 is independently (C1-C10)alkyl or (C6-C10)aryl.
11. The system of claim 5, wherein each occurrence of R1 and R2 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, phenyl, or isomers thereof.
12. The system of claim 11, wherein each occurrence of R1 and R2 is independently methyl, butyl, tert-butyl, octyl, or phenyl.
13. The system of claim 2, wherein M is selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, cerium, praseodymium, neodymium, europium, gadolinium, terbium, dysprosium, copper, holmium, erbium, thulium, and lanthanum.
14. The system of claim 13, wherein M is gadolinium.
15. The system of claim 1, wherein the paramagnetic complex is
16. The system of claim 15, wherein the paramagnetic complex is
17. The system of claim 1, wherein the solvent is selected from the group consisting of acyclic and cyclic hydrocarbons, acyclic and cyclic halo- or per-halo hydrocarbons, aromatic hydrocarbons, acyclic and cyclic ethers, and acyclic and cyclic aldehydes, ketones, esters, amides, sulfides, sulfoxides, and sulfones, and a combination thereof.
18. The system of claim 17, wherein the solvent is pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, tetrachloroethylene, carbon tetrachloride, dichloromethane, trichloromethane, diethyl ether, tetrahydrofuran, ethyl acetate, butyl acetate, or a combination thereof.
19. The system of claim 18, wherein the solvent is hexane, tetrachloroethylene, or a combination thereof.
20. The system of claim 19, wherein the solvent is tetrachloroethylene.
21. The system of claim 1, wherein the system further comprises a camera, or a light source to illuminate the container, or both.
22. The system of claim 1, wherein the container is an open or closed vessel capable of holding the solution.
23. The system of claim 1, wherein the container is made from a glass, a plastic, a polymer, a ceramic, one or more plant-based fibers in a polymer matrix, one or more plant-based fibers in a ceramic matrix, an aerogel, a gel comprising polar or apolar solvents, a non-ferromagnetic, non-ferrimagnetic, or non-paramagnetic metal, or a combination thereof.
24. The system of claim 1, wherein the container is a cuvette, jar, test tube, centrifuge tube, or capillary tube.
25. The system of claim 24, wherein the container is a cuvette.
26. The system of claim 1, wherein the first and second magnets are each independently selected from the group consisting of a permanent magnet, an electromagnet, and a superconducting magnet.
27. The system of claim 26, wherein the first and second magnets are permanent magnets.
28. The system of claim 1, wherein the first and second magnets are each independently neodymium magnets, samarium-cobalt magnets, ferrite magnets, or Alnico magnets.
29. The system of claim 1, wherein the first and second magnets are each independently shaped as a block, a cylinder, a sphere, a disc, or a ring.
30. A method of analyzing a sample comprising one or more solid compounds, the method comprising:
- (a) providing the magnetic levitation system of claim 1;
- (b) depositing the sample in the solution; and
- (c) allowing each of the solid compounds in the sample to migrate to a position in the container indicative of its density.
31. The method of claim 30, further comprising
- (d) analyzing one or more of the solid compounds to determine or confirm its identity.
32. The method of claim 31, wherein step (d) comprises positioning the container such that one or more of the compounds contact the wall of the container and analyzing said compound(s) through the wall of the container using a spectrometer.
33. The method of claim 31, wherein step (d) comprises removing the one or more solid compounds from the container.
34. The method of claim 33, wherein the one or more solid compounds are removed using a pipette, a siphon, a spoon, a spatula, or a small basket.
35. The method of claim 31, wherein the analysis comprises a technique selected from the group consisting of Fourier transform infrared spectroscopy with attenuated total reflectance, mass spectrometry, nuclear magnetic resonance spectroscopy, Raman spectroscopy, X-ray diffractometry, capillary electrophoresis, gas chromatography, ion-mobility spectrometry, liquid chromatography, microcrystalline tests, supercritical fluid chromatography, thin layer chromatography, ultraviolet/visible spectroscopy, microscopy, visual examination, colorimetric tests, fluorescence spectroscopy, immunoassays, melting point analysis, pharmaceutical package inserts, and combinations thereof.
36. The method of claim 35, wherein the technique comprises a portable or handheld device.
37. The method of claim 35, wherein the technique is Fourier transform infrared spectroscopy with attenuated total reflectance, Raman spectroscopy, mass spectrometry, X-ray diffractometry, a colorimetric test, or a combination thereof.
38. The method of claim 35, wherein the Raman spectroscopy is conducted using a portable or handheld device.
39. The method of claim 30, wherein the sample is a crystalline or amorphous sample.
40. The method of claim 30, wherein the sample comprises one or more controlled substances, adulterants, diluents, or a combination thereof.
41. The method of claim 30, wherein the sample comprises fentanyl, acetyl fentanyl, benzyl fentanyl, carfentanyl, cocaine, heroin, oxycodone, methamphetamine, cannabinoids, lysergic acid diethylamide, methaqualone, methadone, hydromorphone, Ritalin, Adderall, peyote, 3,4-methylenedioxymethamphetamine, acetaminophen, caffeine, diltiazem, dipyrone/metamizole, lidocaine, hydroxyzine, levamisole, papaverine, procaine, phenacetin, dimethyl sulfone, D-fructose, D-glucose, α-lactose, D-mannitol, sodium carbonate, starch, including potato starch, sucrose, talc, quinine, butylated hydroxytoluene, hypromellose, polyethylene glycol, polyethylene oxide, magnesium stearate, titanium dioxide, an isomer thereof, a salt thereof, a combination thereof.
42. The method of claim 41, wherein the salt is a sodium, aluminum, potassium, calcium, hydrochloride, citrate, nitrate, sulfate, acetate phosphate, diphosphate, maleate, mesylate, tartrate, or gluconate salt.
43. The method of claim 42, wherein the salt is a hydrochloride salt.
44. The method of claim 30, wherein the sample comprises a salt of fentanyl or caffeine.
45. The method of claim 30, wherein the one or more compounds are present in the sample between 0.01 and 100 weight percent.
46. The method of claim 45, wherein the one or more compounds are present in the sample between 0.01 and 10 weight percent.
47. The method of claim 30, further comprising:
- (e) generating a profile of the position of the one or more compounds relative to the container; and
- (f) generating a database comprising a plurality of profiles, each of which corresponds to a known solid compound or a known mixture of solid compounds.
48. The method of any one of claim 47, wherein the profile of the sample and the profiles of the database are determined at a plurality of time points after the sample is deposited in the solution in step (b).
49. The method of claim 47, further comprising:
- (g) comparing the profile of the sample to the profiles in the database.
50. The method of claim 49, wherein step (g) further comprises determining the identity of the compound based on the comparison.
51. The method of claim 49, wherein step (g) further comprises:
- using a computer to calculate the distances between the generated profile of the sample and the profiles in the database to identify a profile in the database within a minimum distance to the generated profile; wherein the distance is a Euclidian or Mahalanobis distance.
52. The method of claim 49, wherein the profile in the database further comprises the source of the known solid compound or the known mixture of solid compounds and step (g) further comprises determining the source of the sample.
53. The method of claim 49, wherein step (g) further comprises determining the particle size or the mixture of particle sizes of the compound.
54. The method of claim 49, wherein the profile in the database further includes a source of the compound and step (g) further comprises determining the source of the sample.
55. The method of claim 30, wherein the method comprises obtaining and processing spectroscopic, spectrometric, chromatographic, colorimetric, microscopic, photographic, or visual signals of the one or more solid compounds at a position in the container before, at predetermined times during migration, and after migration.
56. The method of claim 55, wherein the method comprises obtaining and processing microscopic or photographic images of the one or more solid compounds at a position in the container before, at predetermined times during migration, and after migration.
57. The method of claim 56, wherein the light intensity of one or more portions of the image before, at predetermined times during migration, and after migration is measured.
58. The method of claim 55, wherein the signals, images, or light intensity measurements of the container are processed by using dynamic time warping, barycenter averaging, machine learning, or a combination thereof.
59. The method of claim 58, wherein the machine learning comprises deep neural networks.
60. The method of claim 59, wherein the machine learning comprises supervised deep learning to train a convolutional neural network on hundreds-to-thousands of signals, images, or light intensity measurements.
61. The method of claim 60, wherein the analysis of unknown mixtures comprises inputting one or more generated signals, images, or light intensity measurements into the trained convolutional neural network and obtaining an output of the identity of the mixture.
Type: Application
Filed: Mar 16, 2020
Publication Date: May 19, 2022
Inventors: Christoffer Karl ABRAHAMSSON (Cambridge, MA), Amit NAGARKAR (Boston, MA), Michael J. FINK (Cambridge, MA), Markus P. NEMITZ (Newton, MA), Daniel J. PRESTON (Cambridge, MA), Shencheng GE (Boston, MA), Joseph BOZENKO (Dulles, VA), George M. WHITESIDES (Newton, MA)
Application Number: 17/439,281